PROJECT SUMMARY Respiratory syncytial virus (RSV) is a leading cause of infant hospitalizations in the U.S., and the disease burden among the elderly is similar to non-pandemic influenza A. Traditional strategies have failed to generate an effective RSV vaccine, and in some instances vaccination resulted in enhanced disease, underscoring the complexity of the human immune response to RSV. Although a prophylactic antibody is available (palivizumab, a humanized mouse mAb marketed by MedImmune as Synagis), its high cost and modest efficacy have restricted its use to high-risk infants. Moreover, due to this high cost, palivizumab is inaccessible to children in developing nations and is unavailable in 4 of the 5 most populous countries ? more than half the world?s population does not have access to this type of treatment. The public health benefit and the worldwide accessibility would undoubtedly be improved by lowering the cost of RSV immunoprophylaxis. In this Phase 2 proposal, the University of Texas at Austin, Adimab (Lebanon, NH), Einstein College of Medicine (The Bronx, NY) and Mapp Biopharmaceutical, Inc. (San Diego, CA), teamed to develop a fully human, highly potent mAb that can be administered in a single dose per RSV season. With a more potent mAb (i.e. lower dose) that can be dosed less frequently (due to extended serum half-life), the team?s objective is to dramatically lower the price and increase the availability of RSV immunoprophylaxis. In addition, competition in the marketplace may also help to reduce costs and increase accessibility globally, especially since palivizumab currently has a monopoly on the RSV market. Our Phase 1 effort identified 3 lead candidates (from a panel of 445 mAbs), all of which are dramatically more potent in vitro and in vivo than palivizumab. Further, these mAbs have similar neutralization activity to AstraZeneca?s second generation RSV mAb MEDI8897 (currently in late stage clinical development) against the 5 RSV strains tested to date. After the success of these Phase 1 efforts, we propose the following Specific Aims for Phase 2: 1) Select a lead candidate based on breadth and potency of neutralization activity against a panel of clinical isolates; 2) Generate a CHO cell line appropriate for GMP manufacture; 3) Manufacture for IND-enabling studies; 4) Conduct IND-enabling studies.